Pharmaceutical composition

ABSTRACT

An ibuprofen-β-cyclodextrin complex for oral consumption in a solution comprising hot water, obtainable by crystallisation from aqueous solution.

This application is a 371 of PCT/GB93/00702 filed Apr. 2, 1993.

This invention relates to a pharmaceutical composition containingibuprofen, a process for its preparation, and a palatable formulationthereof suitable for oral consumption. In particular, the inventionrelates to an ibuprofen-cyclodextrin clathrate complex suitable forformulation in aqueous solution as a hot drink.

Ibuprofen, (±)-2-(p-isobutylphenyl)propionic acid, belongs to the groupof non-steroidal antiinflammatory agents (NSAIDs) and is widelyindicated for the relief of pain and inflammation in disease states suchas arthritis and for treatment of symptoms associated with the commoncold and flu. Formulation of the drug into a preparation suitable fororal administration, in particular into a water-soluble form suitablefor liquid dosing is complicated by its poor water solubility, itsirritating odour and its unpleasant taste. It is an object of thepresent invention to provide a palatable pharmaceutical compositioncontaining ibuprofen formulated for oral dosing as an aqueous solution.

The ability of drug-cyclodextrin complexes to enhance water solubilityand to mask unpleasant taste and odour has been known for many years. Inthis respect, ibuprofen has proved to be very suitable as a candidatefor complexation with cyclodextrins.

Japanese patent publication, JP 56-46837 (Kowa Yakuhin Kogyo) disclosesa method for the preparation of an ibuprofen-β-cyclodextrin clathratecomplex involving the combination of ibuprofen with β-cyclodextrin inwater at elevated temperature and isolation of the clathrate byspray-drying. This method is reported to yield a product containing ahigh percentage of ibuprofen with a molar ratio of ibuprofen toβ-cyclodextrin in excess of 0.7. The increase in water solubility of thedrug is considerable, being raised more than 8-fold from 10.44mg per 100ml to 89.38 mg per 100 ml at 27° C.

The water solubility achieved by complexation with β-cyclodextrin,although significant, is not considered sufficient to permit formulationof ibuprofen as a soluble dosage form for oral administration in liquidform wherein ibuprofen is present at a therapeutic dosage level (100-600mg) in a suitable volume of water (120-250 ml).

European patent publication 274 444 (Bristol Myers) describes thepreparation of ibuprofen-cyclodextrin complexes using α-cyclodextrin,γ-cyclodextrin or a methylated β-cyclodextrin in place ofβ-cyclodextrin. The water solubility of the ibuprofen-cyclodextrincomplex is further enhanced to levels of practical utility using theseforms of cyclodextrin, but the high cost of these materials, reflectedin the cost of medicinal products containing them, is unlikely topromote their widespread use in analgesic products, more particularly inproducts available for self medication for the treatment of minor achesand pains and the symptomatic relief of colds and flu.

United Kingdom patent publication GB 2,219,585 (Reckitt & Colman)discloses a complex of β-cyclodextrin with the sodium, potassium,ammonium, magnesium, calcium, arginine, glycine or lysine salt ofibuprofen, having a molar ratio of ibuprofen to β-cyclodextrin in therange 1:0.2 to 1:0.75 and possessing good water solubility. Thesecomplexes are not entirely suitable for incorporation into formulationsintended for oral consumption in liquid form since, on solution inwater, they confer a somewhat unpleasant, soapy taste, typical of analkaline solution.

The present invention provides an ibuprofen-cydodextrin complex which issuitable for administration as an aqueous solution, which is palatableand yet which is relatively simple and inexpensive to manufacture incomparison with prior art ibuprofen-cyclodextrin complexes.

According to the present invention there is provided the use of anibuprofen-β-cyclodextrin complex for the manufacture of a medicament fororal consumption as an aqueous solution, characterised in that thecomplex is administered in a solution comprising hot water.

It has been found that an approximately 30-fold increase in solubilitycan be achieved by dosing an ibuprofen-β-cyclodextrin complex in aqueoussolution at elevated temperatures. It is therefore possible to achievetherapeutic dosage levels of ibuprofen in solution in a single-doseliquid formulation. An ibuprofen-β-cyclodextrin complex for use in thepresent invention can accommodate a concentration of ibuprofen whichwill deliver a single dose of up to 600 mg in a volume of 200 ml.

Despite the known increase in solubility of many materials in water withincreasing temperature, the practical reality of an ibuprofen liquid hotremedy is surprising. It has been reported that cyclodextrin complexstability constants decrease rapidly with increasing temperature (JACS,101, 1864, (1979) and JCS Perkin Trans., 2, 15, (1984)). It maytherefore be anticipated that dissolution in water as temperature isincreased will be accompanied by a concomitant release of ibuprofen fromthe complex to give an undesirable oily mixture, due to the reduction inthe stability constant for the ibuprofen-β-cyclodextrin complex.Contrary to this expectation, it has now been found thatibuprofen-β-cyclodextrin complexes remain homogeneous and stable inwater up to a temperature of 100° C.

By utilising the enhanced water solubility of ibuprofen-β-cydodextrincomplexes at elevated temperature, there is moreover no necessity fororal administration of solutions at alkaline pH as is necessary for thecyclodextrin complexes described in GB 2, 219,585. According to thepresent invention, ibuprofen-β-cyclodextrin complexes may beadministered as pleasant tasting solutions in the pH range 2.5 to 7.0.

In another aspect of the invention there is provided a process for thepreparation of an ibuprofen-β-cyclodextrin clathrate complex.Ibuprofen-β-cyclodextrin clathrate complexes have previously beenprepared by several methods including co-precipitation, freeze-dryingand neutralisation precipitation methods. Each of these methods requiresthe use of either alkalis or organic solvents; stringent purificationmethods are therefore required. The spray-drying process described in JP56-46837 avoids the use of these reagents; spray-drying is however bothcostly and time consuming. In contrast to the prior art processes, theprocess according to the present invention is both convenient and costeffective as a production method and utilises only water in addition toibuprofen and β-cyclodextrin.

The process according to the invention comprises heating ibuprofen andβ-cyclodextrin in water to form a solution, suitably to a temperature of100° C., followed by crystallisation of the ibuprofen-β-cyclodextrincomplex from the solution thus formed, suitably by maintaining thesolution in the temperature range -5° to 20° C. Ibuprofen-β-cyclodextrincomplexes with an ibuprofen to β-cyclodextrin molar ratio in the range1:1 to 1:3 are obtainable according to the process of the invention.

An ibuprofen-β-cyclodextrin complex obtainable by the process ofcrystallisation from aqueous solution forms an aspect of the presentinvention. Whilst ibuprofen-β-cyclodextrin clathrate complexes preparedby known art methods may be utilised in formulations of the invention,an ibuprofen-β-cyclodextrin complex obtainable by the process ofcrystallisation from aqueous solution is preferred for use in a liquidformulation for oral administration as hereinbefore described.

A complex of the invention may be formulated in any convenient form, forexample as a tablet for solution, or alternatively in powder or granularform for reconstitution with water. Accordingly, the invention providesa pharmaceutical composition comprising an ibuprofen-β-cyclodextrincomplex obtainable by crystallisation from aqueous solution in admixturewith a pharmaceutically acceptable carrier.

Use of an ibuprofen-β-cydodextrin complex as prepared by the process ofthe invention is not limited to oral administration in aqueous solutionat elevated temperature. Complexes of the invention may be formulatedfor oral administration in any convenient form, for example as a swallowor chewable tablet, or as a liquid suspension.

A complex obtainable by crystallisation from aqueous solution may beformulated with any appropriate carrier or adjuvant appropriate to thechosen dosage form. Thus, compositions of the invention may include forexample preservatives, suspending agents, flavouring agents, bulkingagents, binders, adhesives, lubricants, disintegrants, colouring agents,sweetening agents, adsorbents, thickeners and diluents, appropriate totheir form.

Compositions of the invention containing an ibuprofen-β-cydodextrincomplex may in addition include other pharmaceutical agents suitable foradministration therewith, including for example other analgesics,antiinfiammatories and antipyretics and also expectorants,antihistamines, decongestants and antitussive agents, such as forexample phenypropanolamine, phenylephrine, pseudoephedrine,dextromethorphan, caffeine, codeine and ascorbic acid.

The following Examples are illustrative of the invention. Example 5which falls outside the scope of the invention is included forcomparison.

In the Examples, unless otherwise stated, the abbreviation βCD refers toβ-cyclodextrin undecahydrate (β-cyclodextrin. 11H₂ O).

EXAMPLE 1 Preparation of βCD/Ibuprofen Clathrate (2.2:1)

βCD (146.5 g, 110 mM) was dissolved in water (1000 ml) at 100° C.Ibuprofen (10.3 g, 50 mM) was added and the resulting solution was driedon trays in a convection oven at 60° C. for 16 hours. The resultingwhite amorphous product was sieved through a 500 μm screen to yield 132g of powdered βCD/ibuprofen clathrate containing about 7.0% ibuprofen(400 mg ibuprofen per 5714 mg of clathrate).

EXAMPLE 2 Preparation of βCD/Ibuprofen Clathrate (1.1:1)

βCD (146.6 g, 110 mM) was dissolved in water (1000 ml) at 100° C.Ibuprofen (20.6 g, 100 mM) was added and the resulting solution wascooled to 1° C. to give a white crystalling precipitate which was washedwith cold water and dried at 50° C. for 4 hours in a convection oven.The product, a white solid, was sieved through a 500 μm screen to yield125 g of βCD/ibuprofen clathrate, containing about 14% ibuprofen (400 mgibuprofen per 2857 mg of clathrate).

EXAMPLE 3 Preparation of a Pharmaceutical Composition containingIbuprofen/βCD Clathrate for Reconstitution with Hot Water

The following ingredients were sieved through a 500 μm screen and mixedtogether to give a homogeneous white powder:

    ______________________________________    Ibuprofen/βCD Clathrate (Example 1)                              5714 mg    Sucrose                   1876 mg    Sodium Citrate            430 mg    Citric Acid               680 mg    Saccharin Sodium          40 mg    Lemon Flavour             60 mg    Sodium Cyclamate          60 mg    ______________________________________

The resulting powder was dissolved in 150 ml of hot water to give aclear, pleasant tasting solution containing 400 mg of ibuprofen per 150ml of water.

EXAMPLE 4 Preparation of Pharmaceutical Composition containingIbuprofen/βCD Clathrate for Reconstitution with Hot Water

The following ingredients were sieved through a 500 μm screen and mixedtogether to give a homogeneous white powder:

    ______________________________________    Ibuprofen/βCD Clathrate (Example 2)                              2857 mg    Sucrose                   1733 mg    Sodium Citrate            430 mg    Citric Acid               680 mg    Saccharin Sodium          40 mg    Lemon Flavour             200 mg    Sodium Cyclamate          60 mg    ______________________________________

The resulting powder was dissolved in 200 ml of hot water to give aclear, pleasant tasting solution containing 400 mg ibuprofen per 200 mlof water.

EXAMPLE 5 Preparation of a Pharmaceutical Composition containingIbuprofen for Reconstitution with Hot Water

The following ingredients were sieved through a 500 μm screen and mixedtogether to give a homogeneous white powder:

    ______________________________________    Ibuprofen              400 mg    Sucrose                3590 mg    Sodium Citrate         430 mg    Citric Acid            680 mg    Saccharin Sodium       40 mg    Lemon Flavour          200 mg    Sodium Cyclamate       60 mg    ______________________________________

The resulting powder was added to 200 ml of hot water to give a turbidsuspension. The suspension was considered to be organolepticallyunacceptable with a bitter/numbing effect on the oral mucous membrane.

I claim:
 1. A method for oral dosing of ibuprofen comprisingadministering to a patient an ibuprofen-β-cyclodextrin complex in asolution comprising hot water, wherein the ibuprofen β-cyclodextrincomplex delivers a therapeutic dosage level of 100 to 600 mg ibuprofenin solution as a single dosage unit, in a pH range of 2.5 to 7.0, andwherein the β-cyclodextrin of the ibuprofen-β-cyclodextrin complex isderived from β-cyclodextrin undecahydrate.
 2. The method of claim 1wherein the solution additionally comprises one or more of the groupconsisting of a preservative, a suspending agent, a flavouring agent, abulking agent, a binder, an adhesive, a lubricant, a disintegrant, acolouring agent, a sweetening agent, an adsorbent, a thickener and adiluent.
 3. The method of claim 1 wherein the solution additionallycomprises one or more of the group consisting of an analgesic, anantiinflammatory, an antipyretic, an expectorant, an antihistamine, adecongestant and an antitussive.
 4. A composition for oral consumptioncomprising an ibuprofen-β-cyclodextrin complex in hot aqueous solutionhaving a pH in the range 2.5 to 7.0, wherein said composition delivers atherapeutic dosage level of 100 to 600 mg ibuprofen in solution as asingle dosage unit, and further wherein the β-cyclodextrin of theibuprofen-β-cyclodextrin complex is derived from β-cyclodextrinundecahydrate.
 5. The composition of claim 4 further comprising one ormore of the group consisting of a preservative, a suspending agent, aflavouring agent, a bulking agent, a binder, an adhesive, a lubricant, adisintegrant, a colouring agent, a sweetening agent, an adsorbent, athickener and a diluent.
 6. The composition of claim 4 furthercomprising one or more of the group consisting of an analgesic, anantiinflammatory, an antipyretic, an expectorant, an antihistamine, adecongestant and an antitussive.